Center for Alternatives to Animal Testing (CAAT)
Johns Hopkins University, Baltimore, USA –
University of Konstanz, GermanyFrancois Busquet, PhD
Definition of
adverse effects in
EDC toxicology
Outlook
• EU stakeholders mindset• Examples of strategies / point of views of
different actors on adverse effects for edc• IVT challenges to convince the stakeholders
• Regulators want a toolbox that is understandable, sound and reliable (hazard identification, characterization, risk etc…)
• Policy makers (EC + EP) want to protect the sensitive population and ensure sustainable trade (risk management)
• Industry want a toolbox that discriminate accurately the compounds and avoid false positive
• Public opinion wants transparency & action • NGOs want more environment, consumer, workers protection ( =
more in vivo tests) & banning/restriction of suspected molecules• Animal welfare NGOs want NO animal testing• Can the science (endocrinologists, toxicologists, academician..)
do the synthesis? How can we move on based on in vitro tools?
EU Stakeholders Mindset
EXAMPLE OF
STRATEGIES ON
ADVERSE EFFECTS
FOR EDC
EFSA
EFSA JOURNAL 2013; 11 (3)3132 – scientific opinion
ECHA
Peer-Review
Peer-Review
US EDSP
US EDSP
FIFRA: Federal Insecticide, Fungicide, and Rodenticide Act
U.S. Environmental Protection Agency Endocrine Disruptor Screening Program Comprehensive Management Plan
US EDSP
EDSP20
Max $1 million / ingredient
EDSP21
=
in vitro HTS
in silico
Full
replacement
for Tier 1<$30,000 / ingredient
EDSP20
Max $1 million / ingredient
EDSP21
=
in vitro HTS
in silico
Full
replacement
for Tier 1<$30,000 / ingredient
TOXCASTTM
TOXCASTTM
EPA–HQ–OPPT–2015–0305; FRL–9928–69
NEXT TARGET
NEXT TARGET
TIER 2:• AVIAN TWO GENERATION• FISH LIFECYCLE (MEDAKA
MULTIGENERATION TEST)• INVERTEBRATE MYSID LIFECYCLE• MAMMALIAN TWO
GENERATIONS• IN UTERO THROUGH LACTATION
EPA–HQ–OPPT–2015–0305; FRL–9928–69
TiPEDThe Tiered Protocol for Endocrine Disruption
TIPED is not meant to be used
for regulatory actions. It is a
non-exhaustive, flexible
approach where end-users are
chemists.
Schug et al. Designing endocrine disruption out of the next generation of chemicals. Green Chem., 2013, 15, 181
OECD Conceptual
Framework
Previous version 2002
Specific or updated US TIER 1
Not specific devt
Specific or updated
US TIER 1
12 TG adopted in 5 years; time frame 2007 -2012
Not specific devt
Specific or updated
Few comments: •Quantity vs. quality for level4 &level5 => Tinkering?•Permeability with the US EDSP => How to take advantages of recent US Tier1 changes?
US TIER 2
OECD GD150• Level 4:
• B33: The results for a chemical tested in the male or female pubertal assays with only two dose levels may not provide sufficient information on adverse effects. However, for ecological systems, effects on apical endpoints at this level, such as fecundity, would be considered adverse.
• B34: Effects on some endpoints included in the assays can be considered as adverse apical impacts (e.g. major histopathologic changes in reproductive organs in rats; biased phenotypic sex ratios in developing fish)
OECD GD150• Level 5:
• B43: Endpoints sensitive to endocrine disruption, not specified in OECD TG 416, include areola/nipple retention, anogenital distance at birth, measurement of thyroid hormones and TSH levels. Effects on the developing nervous and immune systems are also not (?) assessed.
=> OECD TG 443 (i.e. extended one generation) is presented as the most exhaustive and reliable method to detect EDC: adverse effects are morphological and analytical for mammalian toxicology
In vivo tests
•OPENING THE BLACK BOX
•CONNECTING THE DOTS
•EXTRAPOLATION FROM IN VITRO TO IN VIVO
OECD AOP
OECD AOP
OECD AOP
OECD AOP
AFTER VALIDATING AN AOP, IS IT OK TO GENERATE ONLY IN VITRO DATA
AFTERWARDS?
DRP 178
IVT Challenges (1) to
convince the stakeholders• Looking at sensitive population (time, window)• Looking at brain development (tissue specific) = IQ
loss• Looking at repeated exposure (long-term)• Looking at genital malformations (hypospadia)• Looking for a dose/concentration for extrapolation• Looking at places we have not yet looked at or think
about
IVT Challenges (2) to
convince the stakeholders• What is the purpose of
detection adverse effect in Tox?• => To regulate or so to say filter
“the good, the bad and the ugly” compounds
• Consensus on edc definition & therefore need to display, measure adverse effects in vivo
What to do afterwards
with the workshop?
• November 2015: European Commission
workshop in Brussels organised by DG
ENV? => obvious since it is a LIFE
project?
• ECHA Endocrine Disruptor Expert Group?
• OECD expert group on EDC?
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